Submissions for variant NM_000159.4(GCDH):c.641C>T (p.Thr214Met)

gnomAD frequency: 0.00002  dbSNP: rs1131692030

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493776	SCV000583398	likely pathogenic	not provided	2018-07-27	criteria provided, single submitter	clinical testing	The T214M variant has previously been reported in association with glutaric aciduria type I (GA1) (Naughten et al., 2004; Harting et al., 2009). The T214M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (K210E, P217L, A219T) have been reported in the Human Gene Mutation Database in association with glutaric aciduria type I (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000668340	SCV001396206	pathogenic	Glutaric aciduria, type 1	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 214 of the GCDH protein (p.Thr214Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 19433437, 30217722; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 430567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. This variant disrupts the p.Thr214 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22728054, 24332224). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668340	SCV002555743	likely pathogenic	Glutaric aciduria, type 1	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.641C>T (p.Thr214Met) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251338 control chromosomes. c.641C>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Harting_2009, Serrano Russi_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missesne variants near the variant of interest have been reported in HGMD in association with Glutaric acidaemia 1, suggesting the functional importance of the region. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000668340	SCV003832954	likely pathogenic	Glutaric aciduria, type 1	2021-11-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000668340	SCV004199209	likely pathogenic	Glutaric aciduria, type 1	2023-09-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000668340	SCV000792920	uncertain significance	Glutaric aciduria, type 1	2018-11-27	no assertion criteria provided	clinical testing